The Research Center for Pharmacology and Drug Toxicology: Novel Mechanisms and Pharmacological[unreadable] Consequences of Polyunsaturated Fatty Acid Oxygenation brings together a tightly-knit group of[unreadable] experienced investigators with a shared interest in polyunsaturated fatty acid oxygenation to undertake research[unreadable] focused on the pharmacology, biochemistry, and biology of eicosanoids and related compounds. The goal of[unreadable] this research is to identify new targets for the development of therapies to modulate the formation, metabolism,[unreadable] and biological activities of eicosanoids and related compounds in humans.[unreadable] Studies suggest that oxygenated polyunsaturated fatty acid species play an important role in human physiology[unreadable] and pathophysiology. Thus, pharmacological manipulation of the formation of oxidized species of fatty acids[unreadable] provides the opportunity to prevent or treat pathophysiological processes associated with these compounds.[unreadable] Nonetheless, a thorough understanding, at the molecular level, of factors influencing the formation and actions[unreadable] of eicosanoids and related compounds remains elusive.[unreadable] This Center comprises five research projects and two cores that will provide important insights into the role of[unreadable] oxygenated species of polyunsaturated fatty acids, derived either enzymatically or non-enzymatically, in human[unreadable] physiology and pathophysiology. A strength of our research program is that proposed projects integrate basic[unreadable] pharmacological, biochemical and molecular biological approaches with translational studies involving humans.[unreadable] Project 1 will define biochemical pathways involved in the formation of novel glyceryl-prostaglandins (PGs)[unreadable] from 2-arachidonylglycerol, examine their generation in cells and tissues, and characterize their metabolism in[unreadable] vivo. Project 2 will test the hypothesis that PGD2 receptors are critical modulators of inflammation in the central[unreadable] nervous system using a variety of in vitro and in vivo models. Project 3 builds on findings that acetaminophen[unreadable] inhibits heme protein-catalyzed lipid peroxidation and will determine the molecular basis for this effect. In[unreadable] addition, studies will evaluate the inhibition of lipid peroxidation by acetaminophen-based regimens in humans[unreadable] with subarachnoid hemorrhage. 4-hydroxynonenal is a bioactive lipid derived from the fragmentation of[unreadable] peroxidized polyunsaturated fatty acids that mediates adverse effects of oxidant stress. Project 4 will focus on[unreadable] mechanisms by which this compound is formed in vivo and characterize novel HNE adducts. Project 5 will test[unreadable] the hypothesis that the oxidation of docosahexaenoic can be precisely defined in humans and leads to the[unreadable] formation of here-to-fore undescribed, biologically active, products containing complex cyclic structures. These[unreadable] studies will utilize DNA esterified in phosphatidylethanolamine, a biologically relevant form of this fatty acid.[unreadable] The investigators included in this research proposal are highly integrated both scientifically and intellectually[unreadable] and are extremely experienced in a number of facets of research related to the oxygenation of arachidonate and[unreadable] other polyunsaturated fatty acids. It is anticipated that the projects proposed will significantly advance our[unreadable] understanding of the pharmacology and biology of eicosanoids and related compounds.[unreadable]